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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������_�	����bjbj46bb?���������.�.0<0<0<0<0<����D<D<D<8|<<�=D<�_��>�>�>�>�>�?�?�?,^.^.^.^.^.^.^$�a�SdVR^�0<�F�?�?�F�FR^0<0<�>�>�'_B�W�W�W�FJ0<�>0<�>�\L�W�F,^�W�Wp[�p\�>�������h������Tr<\�\i_H�_V\�doVv�d4p\�d0<p\\�?(�A��W}C<�D��?�?�?R^R^�V�?�?�?�_�F�F�F�F���������������������������������������������������������������������d�?�?�?�?�?�?�?�?�?�.�::Disposition and enterohepatic circulation of intravenously administered 11-nor-9-carboxy-�9-tetrahydrocannabinol in serum and urine in healthy human subjects

Elisabeth B�hnke1a, Lisa Dietz2b, Tilman Heinrich1c, Rolf Aderjan2, Gisela Skopp2, Gerd Mikus1*

1 Department of Clinical Pharmacology and Pharmacoepidemiology, 
University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
2 Institute of Legal and Traffic Medicine, University Hospital, Voss-Str. 2, 69115 Heidelberg, Germany

* Address for correspondence and reprint requests:
Department of Clinical Pharmacology and Pharmacoepidemiology, 
Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Phone: + 49 6221 56 39197, Fax: + 49 6221 56 4642
E-mail: gerd.mikus@med.uni-heidelberg.de

Keywords: Tetrahydrocannabinol, 11-nor-9-carboxy-�9-tetrahydrocannabinol, disposition, enterohepatic circulation 
a current address: Spital Aarberg, Lyss-Strasse 3,13270 Aarberg, Switzerland
b Leibniz-Institut f�r Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Str. 11, 44139 Dortmund, Germany
b current address: Department of Human Genetics, University of Wuerzburg, 97074 Wuerzburg, GermanyAbstract

Purpose: A previously published study on the serum concentration time profile of 11-nor-�9-carboxy-tetrahydrocannabinol (THC-COOH) showed a second peak phenomenon indicating enterohepatic cycling. To elucidate enterohepatic circulation of this major metabolite of �9-tetrahydrocannabinol (THC) following its intravenous administration of a study in 8 healthy male individuals with and without administration of activated charcoal was performed. 
Methods: In a randomized, open, cross-over study with 3 weeks washout, a single dose of 5 mg THC-COOH was administered intravenously over 10 minutes in the presence and absence of 6 x 5 g orally administered, activated charcoal. Serum and urine samples were collected for 7 days following infusion. The concentration of unconjugated and glucuronidated THC-COOH in these samples was determined by gas chromatography/mass spectrometry. Non-parametric pharmacokinetic analysis was carried out using WinNonlin 5.2. 
Results: Enterohepatic circulation of THC-COOH and of its acyl-glucuronide could be shown by interrupting the cycle in the intestine simultaneously decreasing its half-life and window of detection. Administration of charcoal increased the mean systemic clearance by 33 % (5.8 � 1.1 L/h versus 4.3 � 0.8 L/h). The serum half-life of THC-COOH was reduced by 25 % (13.9 � 3.6 h versus 20.4 � 5.7 h). Renal elimination of THC-COOglucuronide was reduced by 17 %. Consequently, the limit of detection was reached on average one day earlier following ingestion of charcoal. 
Conclusions: A significant fraction of the dose of THC-COOH undergoes enterohepatic cycling which can be interrupted by administration of activated charcoal. Consequently, taking of remedies impairing enterohepatic circulation while/after smoking of THC may as well affect THC-COOH or its glucuronide concentrations in serum and urine, impair renal excretion and decrease their time window of detection.


Abbreviations: THC-COOH: 11-nor-�9-carboxy-tetrahydrocannabinol; THC: �9-tetrahydrocannabinol; CYP: cytochrome P450; UGT: uridine 5 -diphospho glucuronosyltransferase, i.v.: intravenous; GC/MS: gas chromatography coupled to mass spectrometry; ECG: electrocardiography; BSTFA: N,O-Bis-(trimethylsilyl)-trifluoracetamide

Introduction
Verification of abstinence from Cannabis use is the second most frequently encountered analytical task beside alcohol misuse in driving cases, conditions of probation and patients during maintenance treatment. In both blood and urine, detection of 11-nor-9-carboxy-�9-tetrahydro-cannabinol (THC-COOH) is most appropriate considering its long half-life. In addition, THC-COOH has been hypothesized to be a marker of the extent of Cannabis use. Nevertheless, there is only limited knowledge on the direct disposition of THC-COOH in humans which is formed from �9-tetrahydrocannabinol (THC) by oxidative breakdown [1, 2]. THC is preferably hydroxylated at the carbon atom of position 11 by CYP2C9 largely depending on dose and route of application [3]. The hydroxyl group undergoes further oxidation to THC-COOH, which is conjugated via uridine 5�-diphospho glucuronosyltransferases (UGTs) 1A1 and 1A3 to form an O-ester-glucuronide [4]. THC-COO-glucuronide is the major metabolic end product eliminated in urine [4-7]. In blood or plasma, mean conjugated THC-COOH is present in higher, but variable quantity compared to mean free THC-COOH [8]. 
Recently, we separately determined the pharmacokinetics and urinary disposition of THC-COOH for the first time after intravenous (i.v.) administration of the metabolite in humans [9, 10]. Some concentration time profiles in serum showed a second peak indicating an enterohepatic circulation of THC-COOH. At present, an enterohepatic cycling of THC metabolites has only tentatively been demonstrated in a dog model but not in humans [11]. Although variable, the elimination half-life of separately administered THC-COOH of as long as 17.6 � 5.2 h may be attributed to its high protein binding [9, 10, 12], activities of UGTs - which, however, exhibit a broad substrate specificity - and a possible enterohepatic cycling. To elucidate whether and to what extent THC-COOH and its glucuronide is cycled between the gut and the systematic circulation thus influencing its elimination, we conducted a study in 8 individuals using activated charcoal to disrupt a possible enterohepatic circulation. 

Materials and Methods
Study Population
The study protocol was approved by the Ethics Committee of the University Hospital, Heidelberg, Germany (L-277/2004) and notified with all necessary documents to the competent authority (Bundesinstitut f�r Arzneimittel und Medizinprodukte, Bonn, Germany). The study was performed at the Department of Clinical Pharmacology and Pharmacoepidemiology in accordance with the Declaration of Helsinki and subsequent amendments. Written informed consent was obtained from each participant.
Eight out of 11 healthy non-smoking male Caucasian individuals (age: 18-50 years; body mass index: 19-30 kg/m2) qualified and were enrolled in the study. Before entry, they had to undergo routine clinical laboratory tests, a physical examination and electrocardiography (ECG). Medical or psychiatric disease, physical dependence or a history of Cannabis-related adverse effects was exclusionary. None of them had a history of regular Cannabis use and assured to be drug-free for at least 6 weeks before entering the study which was further checked by a negative urine test for illicit drugs on the day of admission. 
Study MedicationTHC-COOH (purity 98.7%) was obtained from Lipomed AG (Arlesheim, Switzerland) in brown glass tubes containing 5 mg of the drug metabolite, each. The THC-COOH solution (5 mg at a final volume of 15 mL) was always freshly reconstituted before being infused; details have previously been published [10]. Activated charcoal was provided by Merck (Darmstadt, Germany).
Study ProcedureThe study was conducted as a cross-over study comprising two trial arms: - part A: infusion of 5 mg THC-COOH- part B: infusion of 5 mg THC-COOH and administration of activated charcoal (5 g 15 min before and 5 min, 2, 4, 7 and 10 h after the end of the infusion, respectively, adding up to a total of 30 g charcoal). 
Participants were equally randomized to start with part A or B. After by a wash out phase of at least three weeks participants underwent the second study part. Each part consisted of a 13 h hospitalization on day 1 and a short ambulatory visit each morning of the following seven days. Alcohol and food or beverages with caffeine were not allowed from 24 h before study day 1 until the end of the study week. Subjects arrived in fasting condition at 7 a.m. at the research unit. Standardized lunch and supper (free of extremely fatty food) on study day 1 was provided. For safety reasons, an electrocardiogram monitoring was carried out over 4 h following THC-COOH administration using a Surveyor II monitoring system (Mortara Instruments, Essen, Germany). The participants returned to the unit each morning until 168 h after THC-COOH administration. During that period they maintained their usual daily activities. 
After cannulation of a forearm vein for blood sampling, the participants received 5 mg THC-COOH i.v. via a butterfly cannula placed on the opposite arm. A pilot C infusion pump (Fresenius, Alzenau, Germany) was used to deliver the infusion at a constant rate of 90 mL/h. The tube of the syringe was flushed by a 20% solution of medium chain triglycerides (Lipofundin, Braun, Melsungen, Germany) after infusion has been completed. 
Blood samples (7.5 mL each) were drawn into serum monovettes (Sarstedt, N�mbrecht, Germany) at the following times: immediately before and at the end as well as 15, 20, 25, 30, 40, 55, 70, 100 min and 2, 3, 4, 6, 8, 10, 12, 24, 34, 48, 72, 96, 120, 144 and 168 h after the start of the THC-COOH infusion. After 30 min at room temperature, the samples were centrifuged at 4�C and separated serum was stored at -20�C until analysis. Urine was collected at 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 h. A 10 ml aliquot of each specimen was kept frozen at -20�C until analysis. 
Quantification of Free and Glucuronidated THC-COOH
Deuterated (internal standard, 0.1 mg/mL) and nondeuterated THC-COOH (0.1 mg/mL) was purchased from Promochem (Wesel, Germany). All chemicals including methanol, acetic acid, ethyl acetate, hexane and potassium hydroxide (Roth, Karlsruhe, Germany) were of the highest analytical grade. N,O-Bis-(trimethylsilyl)-trifluoracetamide (BSTFA) containing 1% trimethylchlorsilane was used as the reagent for silylation (Sigma-Aldrich, Steinheim, Germany). Each specimen was processed twice for total and unconjugated THC-COOH, respectively, and subsequently analyzed according to a previously published procedure [13]. 
Briefly, alkaline hydrolysis on urine samples was performed by adding 12 �L 12 M potassium hydroxide to 1 mL of the particular specimen, which was kept at 60�C for 15 min. One mL-aliquots of serum samples were incubated using 2000 U of E. coli glucuronidase (type IX-a, Sigma, Dei�enhofen, Germany; pH 6.8, 50 min, 50�C). Stability of THC-COOH as well as efficiency and completeness of hydrolysis (> 96% for both procedures) has previously been checked [13]. Internal standard was added to hydrolyzed as well as untreated samples, controls and standards (1 mL, respectively) after the pH value had been adjusted to about 4.5. Then, 2 mL of n-hexane/ethyl acetate (9:1 by vol.) was added. Samples were shaken for 10 min, centrifuged (4300 g, 10 min) and the organic layer was taken to dryness in silanized glass vials under a stream of nitrogen. The residue was derivatized with 20 �L of BSTFA (30 min, 60�C). Subsequently samples were transferred into micro-vials for analysis by gas chromatography/mass spectrometry (GC/MS).
One �L was injected into the GC/MS-system (column: CP-Sil 5 CB, 12.5 x 0.2 mm, film thickness 0.4 �m, Chrompack, Middleburg, The Netherlands; GC: Hewlett-Packard series 6890, MS: Hewlett-Packard 5973 MSD, Agilent, Waldbronn, Germany). The initial temperature of the column was 160 �C (2 min hold); then, temperature was increased at a rate of 20 �C/min to 320 �C (2 min hold). The mass spectrometer was operated in the selected ion monitoring mode using ions at m/z 371 (374), 473 (476) and 488 (491) for THC-COOH (deuterated THC-COOH) for identification. The ion ratio of mz 371/374 was used for determination of THC-COOH from authentic and control samples based on a 5 point calibration curve and an additional blank value. The assay has been fully validated using Valistat (Arvecon, Walldorf, Germany); details have been published by Mauden et al. [13]. The lower limit of detection and quantification were 0.3 ng and 1.0 ng/mL THC-COOH/mL for both, serum and urine. 
Pharmacokinetic Calculations and Statistical AnalysisValues are given as mean values; the concentration of glucuronidated THC-COOH was estimated by subtracting the free THC-COOH concentration from the respective total THC-COOH concentration after hydrolysis. The Wilcoxon matched paired signed rank test was used to compare pharmacokinetics between treatments (�=0.05; Prism 5, GraphPad Software Inc, La Jolla, CA 92037 USA).
No sample size calculation was performed due to the exploratory nature of the study. Noncompartmental analysis using WinNonlin 5.2 (Pharsight Corporation, Mountain View, California, USA) was performed to determine the following pharmacokinetic parameters: maximum observed serum concentration (Cmax), time to reach Cmax (Tmax), area under the serum concentration-time curve from time zero to the last measurable concentration (AUC0-168), and area under the serum concentration-time curve extrapolated to infinity (AUC0-") using the linear trapezoidal rule and the terminal elimination half-life (t1/2). The total clearance (Cl) was calculated as the ratio of the intravenous dose to AUC0-"; the volume of distribution (Vz) was based on the terminal elimination phase using the dose divided by the elimination rate constant �z multiplied by AUC0-". 

Results
Non-compartmental Pharmacokinetics
Highest serum concentrations of unconjugated THC-COOH were observed at 0.16 � 0 h without charcoal and at 0.17 � 0.03 h after charcoal administration with respective Cmax of 482.9 � 95.2 �g/L and 517.0 � 67.6 �g/L followed by a quick decline. Figure 1 depicts the mean serum concentration time-profile of THC-COOH in the two groups in the absence and presence of activated charcoal showing a steeper decline in the charcoal group starting at about 6 hours. Free THC-COOH could be quantified up to 72 h after administration in part B and up to 96 h in part A; terminal elimination half-lives averaged 13.9 � 3.6 h (part B) and 20.4 � 5.7 h (part A).
Bound THC-COOH was already detectable after 10 min in 5 subjects as well as after 15 and 20 min in two and one of the participants, respectively. Approximately 50 min after the infusion, the concentration of THC-COOglucuronide was almost of the same order of magnitude as THC-COOH, and, subsequently, was higher during the rest of time. Peak concentrations of 168.9 � 50.9 �g/L or 177.9 � 50.9 �g/L could be noticed at 1.5 � 0.8 h (part B) or at 2.2 � 1.0 h (part A), respectively. All pharmacokinetic parameters calculated from serum values are summarized in table 1. 
Urine 
Analysis of urine samples revealed on average a percentage of the dose of 0.36 % of free THC-COOH and 11.9 % of the acyl glucuronide in part A, whereas lower results - 0.13 % of free THC-COOH and 9.4 % of its glucuronide � could be observed upon treatment with charcoal. In absolute terms, a mean of 595.8 � 306.8 �g and 470.7 � 202.7 �g of the glucuronide metabolite could be recovered from urine in part A and B, respectively, representing a significant difference between groups (Wilcoxon test, p=0.023). Excretion of THC-COOH, however, did not significantly differ between part A and B. Results point to THC-COOglucuronide having partly been adsorbed by the charcoal and being no longer available for renal elimination. The limit of detection (0.3�g THC-COOH/mL urine) was reached within the observation period on average after 138 h in the control group versus 114 h in the charcoal group amounting to a difference of 24 h. Major pharmacokinetic parameters calculated from urine levels are summarized in table 2. 
Tolerability
The study drug was well tolerated; especially, no local inflammation at the infusion site or pain during the infusion was observed. Only 2 adverse drug events occurred which were mild and transient. Participant 8 reported on headache 3 hours after drug administration which resolved the next morning. We also measured a low blood pressure and he was asked to drink some more water. Participant 7 noticed an unknown pain during defecation on day 3 to 8 after intake of activated charcoal. The symptoms resolved spontaneously. 
No changes in ECG parameters were noted during the 4 h monitoring period. There was no clinically relevant influence of the drug on vital signs. Due to technical problems participant 1 received only 4.917 mg THC-COOH in part B and participant 8 only 4.910 mg THC-COOH in part A. 

Discussion
In an investigation primarily aiming at the fate of the parent substance any formed or persisting body burden of metabolites can hardly be estimated or controlled. Addressing forensic problems there is a lack of appropriate investigations coming up along with the use of illicit drugs and subsequent formation of metabolites. This is of special importance when metabolite concentrations are used to detect drug use and assess the manner and frequency of consumption or the time since last use.
THC being a highly lipophilic compound is rapidly distributed and stored in relevant amounts in poorly perfused tissue [14-17] from where the drug slowly redistributes within several days [18].  Thereby, a continuous formation of metabolites occurs which contributes to the rather long elimination half-life of THC-COOH and its glucuronide. Consequently, formation of THC-COOH can be considerably slower than its disposition representing the rate-limiting step in the sequential/parallel processes of drug absorption, distribution and elimination. The "trap" commonly fallen into is that the terminal half-life is mistakenly thought to exemplify terminal drug disposition, when in fact it characterizes drug formation half-life. In contrast, terminal elimination half-life of THC-COOH as a basis to start from might mainly be dependent on the rate of its glucuronidation and other possible oxidative breakdown products [19, 20]. Thus, in humans, the individual body burden of THC, its distribution and redistribution will act as important factors in prolonging elimination and urinary excretion half-lives of THC-COOH. 
The present study provides detailed pharmacokinetics of THC-COOH after administration of 5 mg THC-COOH by the intravenous route into humans for the second time [10] and data about a possible enterohepatic circulation of THC-COOH and its metabolites for the first time. Both, THC-COOH and its glucuronide are acidic metabolites. Therefore, with decreasing pH-value, their octanol/buffer partition coefficient is expected to increase thus facilitating absorption from the duodenum and jejunum [12]. Only one other study has been published in 1981 by Wall and Perez-Reyes [7] reporting on intravenously administered THC-COOH. However, no necessary study details and no pharmacokinetic parameters have been given. The actually estimated pharmacokinetic parameters are in line with our first study on THC-COOH confirming its relative short half-life compared to hitherto published investigations on intravenously applied THC [3, 21].
Concentration time profiles of THC-COOH in serum only slightly differed between subjects; results suggest THC-COOH undergoing enterohepatic cycling. Excretion into bile and enteral reabsorption are the main metabolic steps, sometimes linked to hepatic conjugation and intestinal deconjungation. Recently, it could be shown that THC-COOH along with its glucuronide is most abundant in postmortem bile specimens compared to other body fluids such as blood, urine or cerebrospinal fluid, and that biliary excretion is predominant in the form of the glucuronide [17]. Enterohepatic circulation has been described for endogenous and exogenous compounds, such as bile acids and bilirubin [22] or drugs such as dapsone [23, 24], tricyclic antidepressants [25], estradiol [26] and moxifloxacin [27], respectively. 
Orally given activated charcoal as a nonspecific adsorbent has long been advocated in acute poisoning to reduce absorption of drugs and poisons from the gastrointestinal tract due to its large surface and high adsorption capacity thereby reducing or preventing systemic uptake. Administration of charcoal in doses higher than 30 g was not considered because of the associated increased risk of gastro-intestinal side-effects e.g. constipation. In view of the half-life of THC-COOH the schedule of charcoal administration was designed to maximize its effect on the bioavailability of the drug metabolite [27]. There is evidence from figure 1 that charcoal is effective as from about 6 hours following administration of the first aliquot, though adsorption of THC-COOH and its glucuronide was incomplete. A significant decrease in half-life and AUC could also be noticed for amitriptyline and nortriptyline following repeated doses of charcoal [28]. A similar study aiming on enterohepatic recirculation has been performed by Stass et al.[27] investigating the influence of 10 g activated charcoal on the bioavailability of a single 400 mg-dose of moxifloxacin. Co-administration of charcoal decreased plasma concentrations, but did not change the shape of plasma-concentrations versus time profiles of intravenously given moxifloxacin. The bioavailability of the drug following its administration by the intravenous route was decreased by approximately 20%. Results are also in accordance with those of Neuvonen and Elonen [29] showing that the elimination rate of phenobarbital and carbamazepine is increased by activated charcoal in multiple doses during the post absorption phase. When given in adequately high doses and early enough, activated charcoal almost completely prevents absorption of some drugs, e.g. paracetamol, carbamazepine, phenobarbital, phenylbutazone and theophylline [29-33]. 
The volume of distribution of THC-COOH (table 1) was substantially lower compared with its parent compound of about 700 L [34]. This is consistent with an increase in polarity and hydrophilicity; the octanol/buffer pH 7.4 distribution coefficient of the metabolite averaged 175 whereas that of the parent compound has been measured at 6000 or higher at neutral pH [12]. Related to its estimated volume, the distribution of THC-COOH lasts approximately 12 h which may be due to a high protein binding of THC-COOH of about 92% [12]. In future pharmacokinetic studies on cannabinoids where THC-COOH will be quantified, this time period should be considered.
A long half-life of THC-COOH has been observed in previous studies in which THC was smoked or administered by the intravenous or oral route [11, 21, 35-38]. Slow redistribution of THC from poorly vascularized tissues or other binding sites is responsible for a continuous formation of THC-COOH. After intravenous administration of THC-COOH itself the absence of the flip-flop phenomenon reveals its �true� elimination half-life. This phenomenon was observed previously for midazolam and 1�-hydoxymidazolam where the half-life of the metabolite was estimated at 1 h following separate administration instead of 3 h when formed after administration of the parent compound [38]. The semilogarithmic concentration of THC-COOH follows a straight line after the end of the distribution phase. Therefore, a 96 h observation period seems to be sufficiently long to reliably determine the pharmacokinetics of THC-COOH in the present study. In addition, the limit of detection has also been reached within this time period. Studies assessing the terminal half-life of THC-related THC-COOH should usefully be conducted at least for a period of 6 - 8 anticipated half-lives of THC. 
The total systemic clearance of THC-COOH was low, but increased by about 33 % in part B with an inter-individual variance between 2.8 - 64 % between both groups. Interestingly, the clearance of THC-COOglucuronide did not differ between part A and B. The extensive protein binding of both metabolites may reduce their extractability from serum and contribute to their overall low renal clearance [12]. 
Only 0.15 � 0.09 % of the THC-COOH dose administered has been recovered unchanged in urine over the 96 h collection period. This is in line with an extensive phase II metabolism of THC-COOH [5]. The predominant renal mechanism of elimination of THC-COOH - filtration, secretion or reabsorption - can be elucidated by using published protein binding data of THC-COOH [12] and a glomerular filtration rate of 120 mL/min for healthy subjects. The fraction unbound (0.08) multiplied by the glomerular filtration rate results in 9.6 mL/min. The estimated filtration rate is much higher than the measured renal clearance of 0.14 mL/min suggesting substantial reabsorption of THC-COOH. The mechanism of reabsorption, however, is unknown.
In all oral, inhalative, and smoking THC-studies no information was obtained on the individual amount of THC-COOH formed or about its distribution [21, 35, 36, 39, 40]. Very short half-lives of 2.8 � 4.4 min of its formation have been observed [11] whereas largely different elimination half-lives have been reported being 25-55 hours [34] or 5.2 days for frequent and 6.2 days for infrequent users [21]. Nevertheless, in spite of widely varying serum concentrations observed in smoking studies [35, 41] attempts were made to relate consumption behaviour to a cumulated or decreasing concentration of THC-COOH in serum or the time since last use to THC and THC-COOH based predictive models [42]. However, the distribution and the variability of the volume of distribution of THC-COOH are still unknown. Hence, the body burden of this compound can hardly be calculated which might otherwise enable grossly concluding on the amount of disposable THC. In addition, any disturbance of the gastrointestinal circulation might change the disposition of THC-COOH thus altering detection times in both serum and urine.

Acknowledgement
None of the authors has financial or personal relationships that could potentially be perceived as influencing the research described herein. 
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�/d�gd�A���0�dh^��`�0�gd$�ter 5 mg intravenous administration of THC-CCOH to 10 healthy male individuals without (part A) and with (part B) activated charcoal; Wilc. test*: Wilcoxon matched paired signed rank test, P-values < 0.05 were considered significant; -: non-calculable

THC-COOHTHC-COO-glucuronideParameterPart APart BWilc. test*, PPart APart BWilc. test*, PElimination half-life [h]20.4 � 5.713.9 � 3.6< 0.0523.2 � 6.723.2 � 8.70.844Cmax [�g/L]482.9 � 95.2517.0 � 67.60.055177.9 � 50.9168.9 � 50.90.641AUC0-168 [h*�g/L]1131 � 217856.3 � 177.9< 0.052431 � 7342014 � 6870.078AUC0-( [h*�g/L]1183 � 210903.0 � 194.6< 0.052521 � 7592104 � 6940.078Clearance [L/h]4.3 � 0.85.8 � 1.1(+ 33.3 %)< 0.059.5 � 6.19.8 � 5.30.383Distribution volume [L]128.3 � 43.2111.8 � 43.20.547---Table 2. Major, mean pharmacokinetic parameters (n=8, � SD) of free and conjugated THC-COOH in urine after 5 mg intravenous administration of THC-CCOH to 10 healthy male individuals without (part A) and with (part B) activated charcoal; Wilc. test*: Wilcoxon matched paired signed rank test, P-values < 0.05 were considered significant; -: non-calculable
THC-COOHTHC-COO-glucuronideParameterPart APart BWilc. test*, PPart APart BWilc. test*, PExcreted amount [�g]17.8 � 26.26.6 � 6.30.313595.8 � 306.8470.7 � 202.6< 0.05Elimination half-life [h]---19.0 � 2.914.4 � 3.3< 0.05Renal clearance [mL/min]0.29 � 0.450.14 � 0.150.6404.25 � 1.954.90 � 2.060.945

 SHAPE  \* MERGEFORMAT 


Figure 1:
Mean concentrations of unconjugated THC-COOH [�g/L] after intravenous administration of 5 mg THC-COOH in 8 healthy subjects in the presence and absence of 30g activated charcoal (semilogarithmic presentation)
Table and Figure Legends

Table 1. Mean pharmacokinetic parameters (n=8, � SD) of free and conjugated THC-COOH in serum after 5 mg intravenous administration of THC-CCOH to 10 healthy male individuals without (part A) and with (part B) activated charcoal; Wilc. test*: Wilcoxon matched paired signed rank test, P-values < 0.05 were considered significant; -: non-calculable


Table 2. Major, mean pharmacokinetic parameters (n=8, � SD) of free and conjugated THC-COOH in urine after 5 mg intravenous administration of THC-CCOH to 10 healthy male individuals without (part A) and with (part B) activated charcoal; Wilc. test*: Wilcoxon matched paired signed rank test, P-values < 0.05 were considered significant; -: non-calculable


Figure 1:
Mean concentrations of unconjugated THC-COOH [�g/L] after intravenous administration of 5 mg THC-COOH in 8 healthy subjects in the presence and absence of 30g activated charcoal (semilogarithmic presentation)











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